Heterocyclic M1 Receptor Modulators for Constipation

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Solution Overview

Problem

Current treatments lack effective compounds for modulating cholinergic muscarinic M1 receptors to address constipation associated with neurological diseases, age-related constipation, and opioid-induced constipation.

Innovation Solution

Development of a compound represented by formula (I), which acts as a cholinergic muscarinic M1 receptor positive allosteric modulator, binding to a site different from the endogenous activator acetylcholine to potentiate receptor function.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If conventional treatments are used for constipation, then current therapy options are limited, but effective modulation of cholinergic muscarinic M1 receptors is not achieved

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidreceptor modulation efficacy

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent modifies molecular parameters of the compound structure (formula I) to optimize binding affinity and allosteric modulation at the M1 receptor, achieving effective gastrointestinal motility enhancement without conventional limitations

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The compound acts as an intermediary substance that binds to the M1 receptor at a site distinct from acetylcholine, functioning as a positive allosteric modulator to enhance receptor activity and treat constipation

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If M1 receptor modulators are developed, then constipation treatment effectiveness improves, but compound complexity increases

Engineering Contradiction:

Improveconstipation treatment efficacyVSAvoidcompound structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The compound structure is segmented into specific functional components (formula I with defined substituents R1-R7, X1-X2) where each segment contributes specific pharmacological properties, allowing systematic optimization of efficacy versus complexity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The M1 receptor modulator compound serves multiple functions: it binds to the receptor, potentiates acetylcholine signaling, and specifically treats constipation, making it a multi-functional therapeutic agent

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Power

If positive allosteric modulators are used, then receptor function is potentiated, but specificity for M1 receptor subtype must be maintained

Engineering Contradiction:

Improvereceptor function potentiationVSAvoidreceptor subtype selectivity

Core Design Contradiction:

PowerVSAdaptability or versatility

Solution Approach 1:

The compound exhibits local quality specificity by targeting the M1 receptor subtype with high affinity while maintaining positive allosteric modulation, distinguishing its action from non-selective cholinomimetics and achieving potentiation specific to the M1 receptor

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12024505B2Heterocyclic compounds useful as modulators of acetylcholine receptors

Publication Date: 2024.07.02 TAKEDA PHARMA CO LTD

AI summary

The present invention aims to provide a compound that may be useful for the prophylaxis or treatment of constipation and the like. The present invention provides a compound represented by the following formula (I):wherein each symbol is as described in the specification, or a salt thereof.